The overall goal of the research described in this proposal - carried out in collaboration with Dr. Leo Hollister, Veterans Administration Hospital, Palo Alto, CA 94304 - is (1) to study the slow elimination of delta1-tetrahydrocannabinol (=delta9-THC, "THC") the major psychoactive compound of marijuana - in chronic marihuana smokers as revealed by plasma THC concentrations and urinary THC-metabolite levels. Levels will be monitored for 4 weeks after discontinuation of smoking and to allow unequivocal interpretation each subject will receive a loading dose of deuterium labeled THC. We will also (2) study the metabolite pattern of interindividual differences in the metabolism of THC by semiquantitation analysis of major urinary metabolites after smoking and oral administration of THC to light and heavy users. Possible (3) differences in metabolite pattern with time (during the first 12 h after smoking) will also be assessed. To carry out these studies which have implications for the risk assessment of marijuana but are also of general scientific and forensic interest it is necessary to (4) improve the methodology for stabilizing, separating and assaying urinary THC-metabolites (HPLC) and to (5) synthesize labeled and non-labeled urinary THC-metabolites. We will also attempt to correlate urinary cannabinoid EMIT assays with chemical analysis and also investigate the relative responses of human urinary metabolites in the EMIT assay. We believe we have unique knowledge/experience and facilities which could warrant a grant to a non-US laboratory: e.g. we have identified over 90% of the human urinary THC-metabolites and we have 10 of these in isolated form. We have the only laboratory that routinely and specifically has measured subnanogram plasma levels of THC in man - this is necessary to measure levels of THC after discontinuation of smoking. Grants for the clinical parts of these investigations will be funded separately.